KRAS

Overview

KRAS (Kirsten rat sarcoma viral oncogene homolog) is a gene that encodes a protein belonging to the RAS family of small GTPases, which are critical regulators of cellular signaling pathways involved in cell proliferation, differentiation, and survival. Mutations in the KRAS gene are among the most common oncogenic alterations found in human cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), where they are present in over 90% of cases. The most prevalent mutation, KRASG12D, leads to constitutive activation of downstream signaling pathways, including the MAPK and PI3K/AKT pathways, promoting tumor growth and resistance to therapies. Due to its pivotal role in cancer biology, KRAS has emerged as a significant target for therapeutic intervention.

Focus of Latest Publications

Recent studies have explored multiple therapeutic strategies targeting KRAS-driven cancers through both direct KRAS inhibition and downstream pathway targeting. Novel SOS1 inhibitors, specifically compounds 78b and 78d, demonstrated high SOS1 binding affinity and potently disrupted the SOS1-KRASG12C interaction, inhibiting nucleotide exchange across WT and multiple KRAS variants in colorectal cancer cells. These compounds induced G1 phase arrest and suppressed MAPK and PI3K signaling pathways, achieving significant tumor growth inhibition (75.1% and 86.2%, respectively) in HCT116 xenograft models without toxicity. Alternative approaches include polyisoprenylated cysteinyl amide inhibitors (PCAIs), which disrupted hyperactive mutant KRAS in pancreatic cancer models; NSL-YHJ-2-27 induced apoptosis, inhibited cancer cell migration by over 90%, and doubled caspase 3/7 activity. Direct degradation approaches using proteolysis-targeting chimeras (PROTACs) targeting KRASG12V induced rapid tumor regression in lung adenocarcinoma through both cancer cell-autonomous and microenvironmental mechanisms.

Adaptive resistance to KRAS inhibition has emerged as a key clinical challenge. A combination therapy approach—pairing selective KRAS inhibitors (RMC-6236/daraxonrasib) with EGFR family inhibitors (afatinib) and STAT3 inhibitors (SD36)—induced complete regression of orthotopic pancreatic tumors with no evidence of tumor resistance for over 200 days posttreatment and was well tolerated in preclinical models. Targeted KRAS degradation in lung adenocarcinoma revealed that disease relapse during prolonged PROTAC treatment stemmed primarily from proteolysis machinery dysregulation, representing distinct resistance mechanisms from those occurring with KRAS inhibition alone. Resistance profiling of KRASG12D inhibitors in pancreatic cancer has highlighted the role of EGFR-mediated RAS-MAPK pathway reactivation as a potential adaptive response mechanism.

Genomic and clinical analyses have identified molecular subtypes and co-mutations that influence treatment outcomes. Among patients with advanced lung adenocarcinoma treated with first-line immunochemotherapy, median progression-free survival did not differ significantly across major KRAS subtypes (G12A, G12C, G12D, G12V), nor was it associated with PD-L1 expression levels. However, STK11 co-mutations were enriched in G12C, G12V, and other subtypes and correlated with shorter progression-free survival. In biliary tract cancer, coexistence of TP53 and KRAS mutations identified a molecular subset with poor overall survival after first-line immunochemotherapy. Pancreatic cancer initiation studies revealed that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations.

Emerging methodologies are advancing KRAS-targeted drug discovery and mutation profiling. Deep learning frameworks applied to directed evolution trajectories identified high-order KRAS mutants with potent activities and uncovered hidden allosteric mechanisms, with case studies demonstrating several designed candidates synthesized with nanomolar biochemical potency. A CRISPR-Cas12a-based assay (RECO-Cas) achieved 0.01% variant allele frequency sensitivity for profiling cfDNA mutations, successfully detecting KRAS point mutations in clinical plasma samples with high sensitivity (90.48%) and specificity (100%), supporting early cancer diagnosis and personalized treatment strategies. Additionally, bifunctional ligands targeting c-MYC and KRAS G-quadruplexes showed potent tumor growth inhibition in vivo, promoting CD8+ and CD4+ T lymphocyte responses.